Citations

479 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox. (O’Connell ASCO 2012) In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: US-based oncologists were recruited to complete a survey and contribute treatment data for their last 3 patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the 2 groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed extensively in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

347 Background: 9,704 was the first phase 3 pancreatic cancer trial to validate the prognostic value of postresection CA19-9 for overall survival (OS), with values > 90/180 associated with worse OS. All pts received adjuvant gemcitabine or 5-FU and chemo-radiotherapy (RT). This analysis evaluates patterns of disease failure. Methods: SMS was negative, positive, or unknown. CA19-9 was analyzed at cut points 90, 180 and continuously. LRF and DF were estimated by cumulative incidence and Gray’s test compared. Cox hazard models were used for multivariate analyses (MVA) and included treatment, tumor site, size and nodal status. To adjust for multiple comparisons a p-value < 0.01 is statistically significant and 0.01 to < 0.05 a trend. Results: 538 pts accrued, with 451 eligible and analyzable for SMS and 385 for CA19-9. For CA19-9, 132 (34%) were Lewis Antigen negative (no CA19-9 expression), 200 (52%) < 90 and 220 (57%) < 180. 188 (42%) had negative margins, 152 (34%) positive and 111 (25%) unknown (i.e., no margin comment in path report; shown to have outcomes similar to negative margin pts). Pts with CA19-9 ≥ 180 were more likely to have tumors ≥ 3 cm and pts with positive SMS more likely to have KPS 60 - 80, T3/T4, or N1 disease. On univariate analysis (UVA) CA19-9 cut at 90 was associated with significant increases in both LRF (trend) and DF; in the gemcitabine arm this was seen in DF, not in LRF; in the 5-FU arm it was seen in both. Results were similar at the 180 cut point and continuously. SMS on UVA was not associated with increase in LRF/DF; see Table. On MVA, CA19-9 > 90 was significantly associated with LRF and DF; positive SMS showed only a trend for DF. Conclusions: Postresection CA19-9 has significant association with both LRF and DF not seen with SMS. These findings support continued use of RT in trials and consideration of dose intensification among pts with elevated postresection CA19-9. Grants: NCI U10, CA21661, CA37422, CA180868, CA180822. Clinical trial information: 0000000. [Table: see text]

616 Background: Polybromo-1 (PBRM1) and BRCA1 associated protein-1 (BAP1) are genes commonly mutated in clear cell RCC (ccRCC) and have been associated with clinical outcome. This work aims to evaluate the impact of PBRM1 and BAP1 expression by IHC in mRCC patients treated with VEGF-TT. Methods: PBRM1 and BAP1 expression was evaluated by IHC in a TMA including 146 mRCC patients. PBRM1 and BAP1 IHC scores were dichotomized as a binary variable: negative (-) or positive (+) (weak positivity was excluded). The associations of PBRM1 or BAP1 expression with baseline clinico-pathological characteristics were evaluated, as well as with overall survival (OS) and time to treatment failure (TTF) usingCox proportional hazards models. Results: Out of 146 patients, 116 and 109 samples had available results for PBRM1 and BAP1 staining, respectively. Overall, 90% (n = 131) patients had ccRCC. 70/116 samples (60%) were PBRM1- and 26/109 patients (24%) were BAP1-. Only 12% (n = 13) of patients had simultaneous negative PBRM1 and BAP1. While there was no association between PBRM1 expression status and clinical factors, BAP1- samples were associated with poor IMDC prognostic risk score (p = 0.004) and higher Fuhrman grade (p = 0.012). PBRM1+ patients showed a trend towards an increased risk of death and a shorter TTF compared to PBRM1- patients (OS: HR = 1.38, 95%CI: 0.92-2.07, p = 0.1; TTF: HR = 1.39, 95%CI: 0.94-2.06, p = 0.1). BAP1 expression was not independently associated with OS or TTF. Conclusions: Loss of PBRM1, but not BAP1 expression showed a trend towards longer TTF and OS in mRCC patients treated with VEGF-TT.

220 Background: Paclitaxel is associated with both an acute pain syndrome (P-APS) and chronic chemotherapy-induced peripheral neuropathy (CIPN). Preliminary animal data suggest that minocycline may be effective for the prevention of chemotherapy-induced neurotoxicity. The purpose of this pilot study was to investigate the efficacy of minocycline for the prevention of CIPN and P-APS. Methods: Patients with breast cancer were enrolled prior to initiating neoadjuvant or adjuvant weekly paclitaxel for 12 weeks. They were randomized to receive minocycline 200mg on day 1 followed by 100mg twice daily or a placebo, with the same dosing schedule. Patients completed (1) an acute pain syndrome questionnaire daily during chemotherapy, and (2) the EORTC QLQ-CIPN20 questionnaire at baseline, prior to each dose of paclitaxel, and monthly for 6 months post treatment. The primary goal was to obtain pilot data regarding the possible effect of minocycline on the prevention of paclitaxel-induced CIPN and P-APS, to determine if conducting a larger phase III placebo-controlled trial was indicated. Scores obtained from patient questionnaires were converted to a 0-100 scale, where higher scores = better quality of life. Results: Forty-seven patients were randomized, 45 of which were evaluable, with a mean age of 55. There were no remarkable differences noted between the two groups for the overall sensory score of the EORTC-CIPN 20 or its individual sub-questions, which evaluated tingling, numbness, or shooting burning pain in hands and feet. However, there was a significant difference in the daily average AUC pain score attributed to P-APS, favoring minocycline (median 96.0 vs 84.3; p = 0.02). Correspondingly, patients receiving minocycline used less opioid pain medications for control of P-APS (0% vs 23%, P = 0.05). Not only were no increased toxicities reported with minocycline, but there was an apparent improvement in fatigue (median AUC 76.7 vs 59.0; P = 0.02). Conclusions: Based on the results of this pilot study, minocycline did not appear to be beneficial for the prevention of CIPN, but did look promising for reducing P-APS. Further study of this effect may be warranted. Clinical trial information: NCT02297412.

176 Background: The purpose of the study was to determine the effectiveness of olanzapine (OLN) for the prevention of nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC). Methods: A randomized, double-blind, phase III trial was performed in chemotherapy-naïve patients receiving cisplatin, > 70 mg/m2, or cyclophosphamide-anthracycline-based chemotherapy, comparing OLN to placebo in combination with aprepitant (APR), a 5-HT3 receptor antagonist (5-HT3), and dexamethasone (DEX). The OLN regimen was 10 mg of oral OLN, 125 mg APR, a 5-HT3, and oral DEX 12 mg pre-chemotherapy, day 1, and 10 mg/day of oral OLN and 8 mg DEX on days 2-4 post-chemotherapy plus 80 mg APR on days 2, 3 post-chemotherapy. The placebo (PLA) regimen was oral placebo, pre-chemotherapy, day 1, and on days 2-4 post-chemotherapy; the APR, 5-HT3, and DEX pre- and post-chemotherapy were identical to that used in the OLN regimen. Fosaprepitant (150 mg IV), day 1 was allowed for substitution for the oral aprepitant. Palonosetron, ondansetron, or granisetron were the permitted 5-HT3 options. Nausea was measured on a 0-10 visual analogue scale, with 0 being “no nausea at all” and 10 being “nausea as bad as it can be”. No nausea was the primary endpoint and, complete response (no emesis and no use of rescue medications) was a secondary endpoint. Results: 401 patients (202 OLN, 199 PLA) were enrolled in the study. The proportion of patients who had no nausea was significantly greater for the OLN regimen compared to the PLA regimen for the acute period (24h post-chemotherapy) (74% vs. 45%, p < 0.0006), for the delayed period ( 24-120 h post-chemotherapy) (43% vs. 26%, p < 0.0006), and for the overall period (0-120 h) (39% vs. 22%, p < 0.0006). Complete response was significantly improved for the OLN patients compared to PLA patients for the acute (85% vs. 65%, p < 0.0001), the delayed (67% vs. 53%, p < 0.0078), and the overall periods (64% vs. 41%, p < 0.0001). There were no grade 3 or 4 toxicities. Conclusions: No nausea, the primary endpoint, and complete response, a secondary endpoint, were significantly improved with OLN, compared to PLA. Clinical trial information: NCT02116530.

202 Background: Posttraumatic stress disorder (PTSD) is associated with morbidity and mortality in affected populations. Cancer survivors experience PTSD at a rate higher than the general population, with young age and female gender identified as risk factors. While young women with breast cancer experience greater psychosocial distress in general following diagnosis (dx), little is known about PTSD in this population. Methods: Women dx’d with Stage I-III breast cancer at age ≤ 40 were surveyed as a part of a multi-site cohort study. Demographic, treatment, psychosocial characteristics (including self-reported psychiatric conditions and use of psychiatric medications prior to dx), anxiety and depression (Hospital Anxiety and Depression Scale), fear of recurrence (Lasry Scale), and social support (Medical Outcomes Study) were assessed within 1 year after dx. PTSD was measured at 30 months post-dx using the PTSD Checklist – Civilian Version; a score ≥ 50 was considered positive for PTSD. Univariable and stepwise multivariable logistic regression were used to evaluate factors associated with PTSD. Results: 572 women were eligible for this analysis; median age at dx was 37 (range: 17-40); 87% had Stage I or II cancer. 37/572 women (6.5%) met criteria for PTSD at 30 months. Lower educational attainment, less financial comfort, less social support, stage 2 (vs. 1) disease, receipt of chemotherapy, fear of recurrence, anxiety and depression, and psychiatric comorbidities were associated (p ≤ 0.05) with PTSD in univariable analyses. Chemotherapy (OR = 3.48, 95% CI = 1.09-11.06), anxiety by HADS (OR = 20.29, 95% CI = 7.83-52.53), and psychiatric comorbidities (OR = 4.22, 95% CI = 1.40-12.74) were associated with increased likelihood of PTSD, whereas college education (OR = 0.25, 95% CI = 0.10-0.59) and greater social support (OR = 0.41, 95% CI = 0.17-0.99) appeared to be protective in multivariable analyses. Conclusions: PTSD affects a minority of young breast cancer survivors, with the prevalence in our cohort similar to that seen in other breast cancer populations. Early identification of those at risk for developing PTSD is essential for the adequate treatment of affected women and for the improvement of health outcomes and quality of life in cancer survivors.

175 Background: Inactivity is common in breast cancer survivors and has been linked to poor outcomes. Few trials have tested physical activity (PA) interventions in young women with breast cancer, who may face unique PA barriers due to demands of jobs and young families. Methods: Young and Strong was a cluster-randomized study evaluating the effect of education interventions for young breast cancer survivors.Sites were randomized 1:1 to a young women’s intervention (YWI), focused on fertility and other issues facing young women, or to a physical activity intervention (PAI). At PAI sites, providers were instructed to discuss PA with patients, and participants were given materials to encourage PA. PA was measured with the modified Godin Leisure Score Index at baseline, and 3, 6, and 12 months. Medical records were reviewed to assess provider attention to PA. Changes in weekly min of PA were compared between the PAI and YWI groups using general estimating equations to evaluate clustered binary and Gaussian data. Results: 467 patients enrolled between 7/12 -12/13 across 54 sites. Median age at dx was 40yrs (range 22-45). At baseline, participants were moderately active. PA increased in both groups over time (Table); there was no significant difference in PA between groups at any time (all p > 0.1). Provider attention to PA was documented in 74% of participants on PAI and 61% on YWI (p = 0.15), and correlated with PA at 12 months (median 100 min/wk of PA in participants with provider attention to PA vs. 60 min/wk in those without, p = 0.016). Participants who reported reading all or most the PAI materials reported higher levels of PA vs. those who read less (78% vs. 64%, p = 0.05) Conclusions: Young breast cancer survivors assigned to a PA intervention did not increase PA more than those assigned to an intervention focused on young women’s issues. However, the higher levels of PA among women who engaged with the PAI materials and those whose oncology providers addressed PA suggests the importance of enhancing patient and provider engagement with healthy lifestyle information and recommendations. Clinical trial information: NCT01647607. [Table: see text]

265 Background: UC response to CT is not durable. Angiogenesis may play a role in the progression of UC. We evaluated whether maintenance sunitinib delays progression after response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, stable disease, partial or complete response (SD, PR, CR) after 4-6 cycles of CT for advanced UC were randomized to oral sunitinib 50 mg/day, 28 days on, 14 days off (6-week cycle) or placebo. Disease was assessed every 12 wks. At progression, placebo pts were offered open label sunitinib. Primary endpoint: progression rate at 6 months (ms); secondary endpoints: safety, objective response rate, survival, VEGF/sVEGFR2 serum level changes. Using a randomized selection design 42 pts/arm has 90% probability of selecting sunitinib if true reduction in 6-ms progression rate is 15% (from 50% to 35%). Results: Study was closed early due to slow accrual. 54 pts with median age 69 years, median ECOG PS 1, 70% with bladder primary, 26 with SD, 23 with PR, 5 with CR to CT were randomized to sunitinib (26) or placebo (28). The median number of cycles was 2/arm (sunitinib 0-15, placebo 0-13). The 6-ms progression rate was 81% (95%CI 61-93%), median time-to-progression (TTP) 5 ms (0.3-22.2, 95%CI 2.4-6.3) for sunitinib and 75% (95%CI 55-89%), 2.7 ms (0.8-19.6, 95%CI 2.5-7.4) for placebo. Response rate in pts with SD at enrollment was 9% for sunitinib and 7% for placebo. Most common G3/4 AEs on sunitinib were diarrhea (15.4%/0%), fatigue (15.4%/3.8%), thrombocytopenia (15.4%/7.7%), hypertension (11.5%/0%). 16 placebo pts received sunitinib with best response 1 PR (6.25%), 6 SD (37.5%), 5 PD (31.25%); 4 not response evaluable. Median TTP was 3.4 ms (0.1-22, 95%CI 1.6-5.5). 11 pts had G3/4 AEs, 5 pts discontinued sunitinib due to AEs (4 related, 1 unrelated). Placebo pts had no change in VEGF/sVEGFR2 over time. Sunitinib pts had no change in VEGF but sVEGFR2 significantly decreased after 1 cycle (p<0.0001) and at progression (p=0.0002). VEGF/sVEGFR2 did not correlate with TTP. Conclusions: Maintenance sunitinib was feasible but did not improve 6-ms progression rate; open label sunitinib had limited activity. sVEGFR-2 decreased on sunitinib.

368 Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach. Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method. Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below. Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. [Table: see text] No significant financial relationships to disclose.

367 Background: On initial publication of GI Intergroup RTOG 98-11, concurrent chemoradiation with 5FU+mitomycin (MMC) decreased colostomy failure (CF) vs induction plus concurrent 5FU+cisplatin (CDDP), but did not significantly impact disease free or overall survival (DFS, OS). The intent of the current analysis is to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free [CFS]), CF and relapse (local-regional [LRF], distant [DM]) in this patient group. Methods: Stratification factors included gender, clinical node status, and primary size. DFS/OS were estimated univariately by Kaplan-Meier method and treatment arms compared by log-rank test. Time to relapse/CF were estimated by cumulative incidence method and treatment arms compared by Gray's test. Multivariate analyses were done with Cox proportional hazard models to test for treatment differences, adjusting for stratification factors. Results: Of 682 patients accrued, 649 were analyzable for outcomes. As seen in the table, 5-yr DFS and OS were statistically better for RT+5FU/MMC vs RT+5FU/CDDP (67.7 v 57.6%, p=.0.0045; 78.2 v 70.5%, p=0.021) with trends toward statistical significance for CFS, LRF, and CF (71.8 v 64.9%, p=0.053; 20 v 26.5%, 11.9 v 17.3%, p=0.092 and 0.075). Similar results were seen in multivariate analysis. Conclusions: Concurrent chemoradiation with 5FU-MMC has a statistically significant impact on DFS and OS vs induction + concurrent 5FU-CDDP and borderline significance for CFS, CF and LRF. Therefore, RT+5FU/MMC remains the preferred standard of care. Potential strategies to improve outcomes include treatment intensification and individualized molecular-based treatment. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). [Table: see text] No significant financial relationships to disclose.